A diet well-balanced in macro- and micronutrients is the basis for health and well-being. Together with a healthy lifestyle, including physical activity and exercise, it can prevent or postpone the onset of metabolic diseases. Indeed, an increasing number of column-inches are devoted to the latest ways to improve our disease-free life expectancy.¹

Vitamins are taken by millions of people worldwide every day as nutritional supplements, and are a booming industry. One of these supplements, vitamin B₃, is known to be effective against pellagra, a disease caused by malnutrition. Lately, some preparations of vitamin B₃ have garnered huge attention for their seeming ability to counteract symptoms of metabolic disease and ageing decline in preclinical studies. Let us consider a brief overview of vitamin B₃ metabolism during exercise, and discuss current studies on its supplementation, to see if the hype is true.

FROM VITAMIN B₃ TO NAD

Vitamin B₃ comprises a group of molecules that can act as precursors for the classical enzyme cofactor nicotinamide adenine dinucleotide (NAD), which consists of nicotinic acid (NA), nicotinamide (NAM) and the more recently discovered nicotinamide mononucleotide (NMN)² and nicotinamide riboside (NR).³ NAD is a central mediator of cellular energy metabolism and a crucial link between nutritional intake, cellular metabolism and health.

There are several routes to synthesise NAD. The de novo pathway starts from the essential amino acid tryptophan (Trp). Individuals with vitamin B₆ deficiency are not able to sufficiently metabolise Trp,⁴ pointing to the importance of a well-balanced diet with adequate amounts of necessary micronutrients. The different forms of vitamin B₃ are converted to NAD via shorter enzymatic routes,^5–7 and can refuel NAD in multiple intracellular compartments, including mitochondria. NMN and NR have been extensively tested in preclinical models for their NAD-boosting capability. They are very efficient at increasing NAD levels in many tissues, while circumventing the undesirable side effects of NAM and NA.⁸

WHY NAD IS NEEDED DURING EXERCISE

NAD and its reduced form NADH have a threefold role in human metabolic physiology. First, they are essential coenzymes in redox reactions, e.g. in energy metabolism. During prolonged exercise, muscles have an enhanced demand for energy in the form of adenosine triphosphate (ATP). Muscle mitochondria start to oxidise increased amounts of fuel: glucose mobilised by glycogenolysis in the liver, and fatty acids from lipolysis in adipose tissue. For both, NAD is required to be reduced to NADH in the tricarboxylic acid cycle, to increase ATP production through the electron transport chain. Indeed, both the levels of NAD and expression of an NAD salvage enzyme in muscle were shown to increase during exercise.^9,10

Secondly, NAD is a signalling molecule and substrate for enzymes regulating cellular energy metabolism and stress responses, thereby linking energy metabolism to transcriptional regulation and changes in expression and activity of metabolic regulators. During exercise, ATP is metabolised to adenosine monophosphate (AMP), whilst NADH is concurrently oxidised to NAD to increase ATP production. This state of relative energy deprivation is sensed by master regulators that redirect cellular metabolism to increase fuel for energy production. The AMP-sensing enzyme AMP kinase (AMPK) enhances glucose transport and fatty acid oxidation in acutely exercised muscle.¹¹ Sirtuins are NAD-dependent enzymes that, together with AMPK, activate the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) during prolonged exercise, which leads to enhanced mitochondrial biogenesis in skeletal muscle^12,13 and gearing of whole-body energy metabolism towards energy production.¹⁴

Thirdly, the phosphorylated form of NAD, nicotinamide adenine dinucleotide phosphate (NADP/NADPH), plays an important role in oxidative stress defence. An example of this is the requirement for NADPH during exercise, when the increased demand for energy causes enhanced mitochondrial production of reactive oxygen species. In this scenario, vitamin B₃ could be useful towards refuelling depleted NAD levels to meet the increased demand and helping to maintain sirtuin activity.

VITAMIN B₃ SUPPLEMENTATION AND NAD REPLETION

In preclinical models of ageing, nutritional insults (high fat–high sucrose diet, alcohol) and various metabolic disorders such as obesity, type 2 diabetes or fatty liver disease, NAD is often severely depleted to levels that impair redox metabolism and reduce the activity of sirtuins.¹⁵ In numerous studies, repletion of NAD with NR or NMN successfully reversed the negative effects of ageing or diet-induced obesity in mice.¹⁶ The importance of NAD homeostasis in mouse skeletal muscle was shown using a model of genetic depletion, which resulted in decreased muscle strength and endurance exercise performance and could be counteracted by supplementation with NR.¹⁷ The main cause for this beneficial effect was shown to be improved mitochondrial function.^18,19

Since NAD repletion was found to be a promising therapeutic route in preclinical models, human clinical trials were started, examining the effects in mildly obese or aged, otherwise healthy, males. NR was found to be a safe way to increase NAD in blood, when applied for short durations,^20–22 while a clinical trial for NMN focusing on cardiometabolic health has recently been completed.²³ To date, short term NR supplementation in humans is safe and well tolerated; however, in contrast to preclinical models, measures of whole-body energy metabolism, muscle strength and cardiac or endocrine function in humans were not improved.^{20,21,24–28}

COULD NAD REPLETION BOOST EXERCISE PERFORMANCE?

Diets low in micronutrients and vitamins can lead to compromised health through depletion of NAD availability and impaired resilience to metabolic stress. However, until recently, no study had specifically examined whether increased amounts of vitamin B₃, or indeed vitamin B₃ taken as single supplement, are needed or are beneficial during physical activity in humans.

In mice, supplementation with NR was shown to increase exercise capacity, running distance and ATP production in muscle of lean and diet-induced obese mice.¹⁸ Conversely, studies in rats found a decrease in exercise capacity and altered energy metabolism.^29,30

In human skeletal muscle, supplementation with NR can augment the NAD metabolome and lead to transcriptional adaptations of energy metabolic genes. A recent study examined exercise performance after NR supplementation in young and old individuals and showed decreased oxidative stress and improved physical performance in old, but not young, subjects.³¹ These data hint towards the need for an individualised approach for NAD repletion only in individuals with pre-existing NAD depletion, which might also be tissue-specific. Carefully designed studies with longer durations, that take into account the type of exercise, will be necessary to tease out potential positive effects of NAD repletion on exercise performance. Future clinical trials should also address the question of whether muscle NAD levels are actually decreased, as in a recent study including individuals with sarcopenia.³²

IN CONCLUSION

There is no doubt that it is better to consume a well-balanced diet as part of a healthy lifestyle than to consume supplements. Currently, there are limited data or evidence for using vitamin B₃ supplements to increase physical performance or to gain other health benefits in humans. Both athletes and the general public should wait for the results of further clinical trials that are exploring the combined effects of NR supplements and exercise on skeletal muscle and mitochondrial function in healthy individuals³³ or patients with hypertension,³⁴ to determine if NAD repletion could potentially be beneficial for humans.

Antje Garten, Senior Researcher, Center for Pediatric Research, Leipzig University, Germany

REFERENCES

1. Anonymous 2020 The Guardian www.theguardian.com/society/2020/jan/08/healthy-habits-extend-disease-free-life-by-up-to-a-decade.
2. Revollo JR et al. 2004 Journal of Biological Chemistry 279 50754–50763.
3. Bieganowski P et al. 2004 Cell 117 495–502.
4. Sauberlich HE 1980 Annals of the New York Academy of Sciences 355 80–97.
5. Fletcher RS et al. 2017 Molecular Metabolism 6 819–832.
6. Kulikova VA et al. 2018 Biochemistry 83 800–812.
7. Grozio A et al. 2019 Nature Metabolism 1 47–57.
8. van de Weijer T et al. 2015 Diabetes 64 1193–1201.
9. de Guia RM et al. 2019 Physiological Reports 7 e14139.
10. Mancini A et al. 2017 European Journal of Applied Physiology 117 721–730.
11. Viollet B 2017 In Hormones, Metabolism and the Benefits of Exercise pp 13–24. Ed B Spiegelman. Cham, Switzerland: Springer.
12. Cantó C et al. 2009 Nature 458 1056–1060.
13. Wu Z et al. 1999 Cell 98 115–124.
14. Rodgers JT et al. 2008 FEBS Letters 582 46–53.
15. Cantó C et al. 2015 Cell Metabolism 22 31–53.
16. Elhassan YS et al. 2017 Journal of the Endocrine Society 1 816–835.
17. Frederick DW et al. 2016 Cell Metabolism 24 269–282.
18. Cantó C et al. 2012 Cell Metabolism 15 838–847.
19. Mills KF et al. 2016 Cell Metabolism 24 1–12.
20. Airhart SE et al. 2017 PLoS One 12 e0186459.
21. Trammell SAJ et al. 2016 Nature Communications 7 12948.
22. Conze D et al. 2019 Science Reports 9 9772.
23. Washington University School of Medicine 2017 Effect of Nicotinamide Mononucleotide (NMN) on Cardiometabolic Function www.clinicaltrials.gov/ct2/show/NCT03151239.
24. Martens CCR et al. 2018 Nature Communications 9 1286.
25. Dollerup OL et al. 2019 Journal of Physiology doi: 10.1113/JP278752.
26. Dollerup OL et al. 2018 American Journal of Clinical Nutrition 108 343–353.
27. Dollerup OL et al. 2019 Journal of Clinical Endocrinology & Metabolism 104 5703–5714.
28. Elhassan YS et al. 2019 Cell Reports 28 1717–1728.e6.
29. Kourtzidis IA et al. 2016 Journal of the International Society of Sports Nutrition 13 32.
30. Kourtzidis IA et al. 2018 Experimental Physiology 103 1357–1366.
31. Dolopikou CF et al. 2019 European Journal of Nutrition doi: 10.1007/s00394-01901919-4.
32. Migliavacca E et al. 2019 Nature Communications 10 5808.
33. Elysium Health 2019 Effect of Basis^TM and High Intensity Interval Training (HIIT) on Muscle Metabolism and Exercise Performance www.clinicaltrials.gov/ct2/show/NCT04050358.
34. University of Florida 2019 Nicotinamide Riboside as an Enhancer of Exercise Therapy in Hypertensive Older Adults (The NEET Trial) www.clinicaltrials.gov/ct2/show/NCT04112043.